Human Herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV) and human herpesvirus (HHV6) are members ofthe herpesvirus family and are included on the NIAID list of Emerging/Re-Emerging pathogens. HHV8/KSHV is associated with three different cancers in the human population including Kaposi's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. In Sub-Saharan Africa, KS is the most common cancer in men. Human herpesvirus type-6 (HHV-6) is the infectious cause of roseola infantum in young children. In response to RFA-AI-12-048, Immune mechanisms of Viral Control, we propose to determine how DNA herpes viruses are sensed by the host immune system. We propose to determine the interaction of multiple pathogen recognition receptors (PRRs) with these DNA viruses and the mechanisms by which these viruses are sensed by host PRRs to activate the innate immune response. We hypothesize that PRRs involved in nucleic acid sensing of viral genomes are able to detect KSHV and HHV6 and activate innate immune responses. Additionally, the DNA damage response induced by herpes viral infection may also contribute to activation of innate immune pathways. This project advances the overall goals of the program by using cutting edge quantitative proteomic approaches to identify novel paradigm shifting pathways of pathogen sensing, identifying nucleic acid binding by human PRRs, and determining cross-talk between multiple PRRs in the host response to NIAID Emerging/Reemerging viruses.